Glucagon receptor antibody as an add-on to type 1 therapy?

This is an interesting concept but it also seems incredibly dangerous – disabling or muting the body’s already impaired glucagon response seems like it could backfire in any number of situations.

Site needs a logon. But without reading it, it seems odd that somebody would WANT to disable a Glucagon response? I can often times see the Glucagon response on the CGM and it is great when that kicks in. I think it is helpful to stabilize the BG under specific circumstances.

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So if you do a Google News search it will let you read the whole article without logging in :slight_smile:

Some excerpts:
SAN DIEGO — An investigational glucagon receptor agonist — the human antibody REMD-477 (REMD Biotherapeutics) — has shown promise in a 26-day, phase 1 study of patients with type 1 diabetes.
Specifically, those who received a single subcutaneous injection of REMD-477 used less insulin each day, and their glucose levels were in the target range 15% more often than seen in patients who received placebo, in the first days after the injection. Adverse effects were mild or moderate, and there were no statistically significant differences in the rate of hypoglycemia.
This proof-of-concept study “support[s] the long-standing theory that blocking glucagon can have a significant clinical impact in patients with type 1 diabetes,” Jeremy Pettus, MD, from the University of California San Diego, told the press prior to his presentation to the President’s Oral Session at the American Diabetes Association (ADA) 77th Scientific Sessions last week.
“I think [this research is] encouraging but preliminary,” session co-chair Alvin C. Powers, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, told Medscape Medical News. If this antibody or another agent could safely modulate the effects of glucagon without increasing the rate of hypoglycemia, “that would be an advantage,” and this could someday perhaps be an add-on therapy for type 1 diabetes, he said.

Then this:

Glucagon Secretion Extremely Disrupted in Type 1 Diabetes

Glucagon is the hormone that prevents blood glucose levels from falling too low by causing the liver to convert stored glycogen into glucose and releasing this into the bloodstream.
But in type 1 diabetes, glucagon secretion is “extremely dysregulated,” and it is secreted not in response to hypoglycemia but rather to hyperglycemia — which may explain some of the “chaos” in type 1 diabetes, glucose levels fluctuate wildly, explained Dr Pettus.
Describing some preclinical work in mice models that lacked pancreatic β cells and couldn’t produce insulin, REMD-477 — an antibody that blocks glucagon receptor signaling and reduces glucose output from the liver — had “a remarkable effect” of lowering blood glucose without insulin administration, he told delegates.
In the current human trial, he and his colleagues hypothesized that patients with type 1 diabetes who received a single 70-mg subcutaneous dose of this agent would require less daily insulin to maintain glycemic control.

The small study did not note an increase in hypoglycemia:
On days 6 to 12, patients who had received the glucagon receptor agonist injection spent more time in the target glycemic range than did the other patients: 71% vs 56% of the time, for a difference of 15 percentage points (P = .001), or 3.5 hours/day.
Patients who had received the antibody injection also spent less time being hyperglycemic than the other patients: 23% vs 39% of the time (P = .001). But patients in both groups spent a similar amount of time in hypoglycemia (5% and 6% of the time).

I don’t buy that statement without substantially more human evidence.

@TiaG - I agree with your original assessment.

So here is the study they are seeming to draw from

And on the second page there’s this:

In nondiabetic subjects, a glucose load suppresses glucagon
levels by stimulating an acute transient rise in paracrine insulin
from β-cells juxtaposed to the glucagon-producing α cells (4–6).
This glucagon suppression converts the liver from an organ of
glucose production to an organ of glucose storage (7). In T1D,
paracrine insulin is lacking and is replaced by peripherally
injected insulin. The resulting intraislet insulin concentrations
are but a small fraction of the paracrine concentrations of undiluted
insulin that suppress glucagon in nondiabetic subjects (8,
9). In 1974, it was reported that hyperglycemia paradoxically
stimulates glucagon secretion in dogs with chemically induced
diabetes (10). More recently, plasma glucagon concentrations
were reported to rise, with a tripling of hepatic glucose production,
in normal rats continuously infused with glucose at
a constant rate (11). Thus, there is evidence that in the absence
of adequate insulin, elevated glucose might stimulate glucagon production, which in turn aggravates hyperglycemia. In this setting,
the liver would not be reprogrammed to store incoming
glucose but, rather, would continue to produce glucose as if it
were still in the unfed state (12). This may play a major role in
postprandial hyperglycemia (10).

If you really want to go down the rabbit hole to understand the glucagon response and see how plausible this idea is, the citations that paper uses are:
7. Moore MC, Coate KC, Winnick JJ, An Z, Cherrington AD (2012) Regulation of hepatic
glucose uptake and storage in vivo. Adv Nutr 3(3):286–294.
8. Unger RH, Cherrington AD (2012) Glucagonocentric restructuring of diabetes: A
pathophysiologic and therapeutic makeover. J Clin Invest 122(1):4–12.
9. Unger RH, Roth MG (2015) A New Biology of Diabetes Revealed by Leptin. Cell Metab
10. Braaten JT, Faloona GR, Unger RH (1974) The effect of insulin on the alpha-cell response
to hyperglycemia in long-standing alloxan diabetes. J Clin Invest 53(4):
11. Jamison RA, et al. (2011) Hyperglucagonemia precedes a decline in insulin secretion
and causes hyperglycemia in chronically glucose-infused rats. Am J Physiol Endocrinol
Metab 301(6):E1174–E1183.
12. Cherrington AD, Lacy WW, Chiasson JL (1978) Effect of glucagon on glucose production
during insulin deficiency in the dog. J Clin Invest 62(3):664–677.

Anyways, I don’t doubt that glucagon response is messed up in Type 1 diabetics – it’s simply the geography of the pancreas and how alpha cells detect and respond to low blood sugar levels (indirectly, through the action of insulin release from beta cells).

It’s more that I am just skeptical that there are NO circumstances when your body might need that glucagon response. For instance, what if someone was given the wrong dose of insulin and then you injected glucagon to cause a rise in response? Would this antibody block those effects?

So I can imagine this being okay for day-to-day occurences but potentially being like newer blood thinners where there is no anti-clotting reversal mechanism – your’e flying without the safety parachute.

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